Apolipoprotein (apo) A-I is the major protein constituent of plasma high density lipoproteins (HDL). HDL has been shown to promote cholesterol efflux from cells in vitro. Decreased plasma concentrations of HDL cholesterol and apoA-I have been associated with premature coronary artery disease (CAD) due to atherosclerosis in our society. Genetic HDL deficiency (familial hypoalphalipoproteinemia) appears to be fairly common in patients with premature CAD. The gene for apoA-I has been isolated and characterized. Our preliminary studies indicate that a specific apoA-I gene polymorphism, detected following Pst I restriction enzyme digestion utilizing a specific probe, is significantly more common in subjects with premature CAD (32.8%) than in normal control subjects (3.9%), and in some kindreds is associated with genetic HDL deficiency. This apoA-I gene polymorphism is due to an alteration in the apoA-I, apoC-III intergenic region, near the 3' end of the coding region for ApoA-I. Our specific aims are: 1) to determine the prevalence of genetic HDL cholesterol and apoA-I deficiency and the Pst I apoA-I gene polymorphism in patients with premature CAD and their first degree relatives utilizing standard lipid analysis, immunoassay and Southern blotting; 2) to assess whether the risk of developing premature CAD is associated with the gene polymorphism; 3) to ascertain the relationship between HDL deficiency, the Pst I gene polymorphism, and premature CAD by linkage analysis; 4) to isolate and characterize the abnormal apoA-I, apoC-III gene complex by gene mapping studies with multiple restriction enzymes, and by cloning and sequencing methods. These studies will allow us to test the following hypotheses: 1. The Pst I apoA-I gene polymorphism is associated with genetic HDL deficiency and premature CAD; 2. Genetic HDL deficiency associated with the Pst I apoA-I gene polymorphism is a common familial lipoprotein disorder in patients with premature CAD; 3. The Pst I apoA-I gene polymorphism is due to a specific mutation in the apoA-I, apoC-III intergenic region, which directly or indirectly (via a linked polymorphism) affects apoA-I synthesis.